Purpose: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results we designed a randomized phase III trial to investigate the FLASH effect in cat-patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-RT was studied on mini-pigs using large field irradiation. Experimental Design: Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to 2 arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10x4.8 Gy (90% isodose), arm 2 used 1x30 Gy (90% isodose) FLASH. Mini-pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH Results: In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis which occurred 9-15 months after RT in 3/7 cats treated with FLASH-RT (43%), as compared to 0/9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded but severe late skin necrosis occurred in a volume-dependent manner (7-9 months) which later resolved. Conclusions: The reported outcomes point to the caveats of translating single-high-dose FLASH-RT and emphasizes the need for caution and further investigations.

Visual impairment from radiation‐induced damage can be painful, disabling, and reduces the patient's quality of life. Ocular tissue damage can result from the proximity of ocular organs at risk to irradiated sinonasal target volumes. As toxicity depends on the radiation dose delivered to a certain volume, dose‐volume constraints for organs at risk should ideally be known during treatment planning in order to reduce toxicity. Herein, we summarize published ocular toxicity data of dogs irradiated for sinonasal tumors from 36 publications (1976‐2018). In particular, we tried to extract a dose guideline for a clinically acceptable rate of ocular toxicity. The side effects to ocular and periocular tissues were reported in 26/36 studies (72%) and graded according to scoring systems (10/26; 39%). With most scoring systems, however, toxicities of different ocular and periocular tissues are summed into one score. Further, the scores were mostly applied in retrospect and lack volume‐ and dose‐data. This incomplete information reflects the crux of the matter for radiation dose tolerance in canine ocular tissues: The published information of the last three decades does not allow formulating dose‐volume guidelines. As a start, we can only state that a mean dose of 39 Gy (given in 10 x 4.2 Gy fractions) will lead to loss of vision by one or both eyes, while mean doses of <30 Gy seem to preserve functionality. With a future goal to define tolerated doses and volumes of ocular and periocular tissues at risk, we propose the use of combined ocular toxicity scoring systems.

Planning organ at risk volume (PRV) estimates have been reported as methods for sparing organs at risk (OARs) during radiation therapy, especially for hypofractioned and/or dose‐escalated protocols. The objectives of this retrospective, analytical, observational study were to evaluate peri‐ocular OAR shifts and derive PRVs in a sample of dogs undergoing radiation therapy for periocular tumors. Inclusion criteria were as follows: dogs irradiated for periocular tumors, with 3D‐image‐guidance and at least four cone‐beam CTs (CBCTs) used for position verification, and positioning in a rigid bite block immobilization device. Peri‐ocular OARs were contoured on each CBCT and the systematic and random error of the shifts in relation to the planning CT position computed. The formula 1.3×Σ+0.5xσ was used to generate a PRV of each OAR in the dorsoventral, mediolateral, and craniocaudal axis. A total of 30 dogs were sampled, with 450 OARs contoured, and 2145 shifts assessed. The PRV expansion was qualitatively different for each organ (1‐4 mm for the dorsoventral and 1‐2 mm for the mediolateral and craniocaudal axes). Maximal PRV expansion was ≤4 mm and directional for the majority; most pronounced for corneas and retinas. Findings from the current study may help improve awareness of and minimization of radiation dose in peri‐ocular OARs for future canine patients. Because some OARs were difficult to visualize on CBCTs and/ or to delineate on the planning CT, authors recommend that PRV estimates be institution‐specific and applied with caution.

Supplementary Table from Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs

Supplementary Table from Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs